Back to EveryPatent.com
United States Patent |
5,648,536
|
Dunn
,   et al.
|
July 15, 1997
|
Process for producing ioversol
Abstract
The present invention discloses a new process for producing ioversol
(marketed as OPTIRAY.RTM.) comprising:
(a) reacting
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with
chloroacetyl chloride in a polar aprotic solvent, or combinations thereof,
to produce
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiod
oisophthalamide;
(b) reacting the product of (a) with sodium hydroxide to produce
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisopthala
mide;
(c) reacting the product of (b) in water and sodium acetate to produce
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide;
and
(d) reacting the product of (c) with an alkylating agent capable of
producing hydroxylhylated product in the presence of a base and water to
produce ioversol.
Inventors:
|
Dunn; Thomas Jeffrey (9505 Byrnesville Rd., Cedar Hill, MO 63016);
White; David H. (877 Gardenway Dr., Ballwin, MO 63011);
Kneller; Mills Thomas (7314 Colgate Ave., University City, MO 63130);
Jones; Michelle M. (16212 Copperwood La., Grover, MO 63040);
Doran, III; Narciso Ocampo (3766 Vincentian La., Bridgeton, MO 63044)
|
Appl. No.:
|
482380 |
Filed:
|
June 7, 1995 |
Current U.S. Class: |
564/153; 424/9.454; 564/133 |
Intern'l Class: |
C07C 233/65; C07C 231/02 |
Field of Search: |
564/153,133
424/9.454
|
References Cited
U.S. Patent Documents
4396598 | Aug., 1983 | Lin | 424/5.
|
5177261 | Jan., 1993 | McCarthy et al. | 564/153.
|
5256393 | Oct., 1993 | McCarthy et al. | 424/5.
|
5371278 | Dec., 1994 | McCarthy et al. | 560/251.
|
Foreign Patent Documents |
1198739 | Dec., 1985 | CA.
| |
Primary Examiner: Kumar; Shailendra
Attorney, Agent or Firm: Stierwalt; Brian K.
Claims
What is claimed is:
1. A process for producing ioversol comprising:
(a) reacting
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with
chloroacetyl chloride in a polar aprotic solvent, or combinations thereof,
to produce
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido-2,4,6-triiodo
isophthalamide;
(b) reacting the product of (a) with sodium hydroxide to produce
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisopthala
mide;
(c) reacting the product of (b) in water and sodium acetate to produce
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide;
and
(d) reacting the product of (c) with an alkylating agent capable of
producing a hydroxyethylated product in the presence of a base and water
to produce ioversol.
2. The process of claim 1 wherein the polar aprotic solvent is selected
from dimethylacetamide, acetonitrile, dimethylsulfoxide,
dimethylformamide, tetrahydrofuran, dimethoxyethane, acetonitrile, or
mixtures thereof.
3. The process of claim 2 wherein the polar aprotic solvent is
N,N-dimethylacetamide.
4. The process of claim 2 wherein the polar aprotic solvent is
N,N-dimethylacetamide and acetonitrile.
5. The process of claim 1 wherein the alkylating agent in (d) is selected
from the group consisting of 2-chloroethanol, ethylene oxide, ethylene
carbonate, 2-bromoethanol, 2-iodoethanol and 2-tosylethanol.
6. The process of claim 5 wherein the alkylating agent is ethylene oxide.
7. The process of claim 1 wherein the base in (d) is selected from sodium
hydroxide, lithium hydroxide, ammonium hydroxide and potassium hydroxide.
8. The process of claim 7 wherein the base is sodium hydroxide.
9. A process for producing ioversol comprising:
(a) reacting
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with
chloroacetyl chloride in N,N-dimethylacetamide to produce
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiod
oisophthalamide;
(b) reacting the product of (a) with sodium hydroxide to produce
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisopthala
mide;
(c) reacting the product of (b) in water and sodium acetate to produce
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide;
and
(d) reacting the product of (c) with sodium hydroxide, water, and ethylene
oxide, to produce ioversol.
10. A process for producing ioversol comprising:
(a) reacting
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with
chloroacetyl chloride in N,N-dimethylacetamide and acetonitrile, to
produce N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,
6-triiodoisophthalamide;
(b) reacting the product of (a) with sodium hydroxide to produce
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisopthala
mide;
(c) reacting the product of (b) in water and sodium acetate to produce
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide;
and
(d) reacting the product of (c) with sodium hydroxide, water, and ethylene
oxide, to produce ioversol.
Description
FIELD OF THE INVENTION
This invention is in the field of imaging. In particular, the invention
relates to X-ray imaging. And most particularly, the invention relates to
a new process for obtaining ioversol.
BACKGROUND OF THE INVENTION
This invention relates to
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod
oisopthalamide (ioversol).
Ioversol is commonly used as an X-ray contrast agent. The agent may be used
in various radiographic procedures including those involving cardiography,
coronary arteriography, aortography, cerebral and peripheral angiography,
arthrography, intravenous pyelography and urography as well as
myelography.
The present commercial manufacture of ioversol proceeds in four steps from
bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-aminoisophthalamide to crude
ioversol product, which product is subsequently purified. This conversion
utilizes two expensive raw materials, acetoxyacetyl chloride (AAC) and
bromoethylacetate (BEA), which together contribute to greater than 25% of
the final product material cost. Additionally, the present commercial
manufacturing process requires the use of several expensive,
environmentally undesirable and/or reactive solvents such as
1,1,2-trichloroethane (TCE), dimethylsulfoxide (DMSO) and amylacetate.
Each of these solvents have been particularly troublesome in manufacturing
due to difficulties in recovery and other operational difficulties. TCE,
in particular, is a chlorinated solvent of considerable concern in
manufacturing. Thus, there exists a need for an improved process for the
manufacture of ioversol which incorporates less expensive and more
environmentally suitable raw materials.
SUMMARY OF THE INVENTION
The present invention provides a new process for producing ioversol
(marketed as OPTIRAY.RTM.) comprising:
(a) reacting
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with
chloroacetyl chloride in a polar aprotic solvent or combinations thereof
to produce
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiod
oisophthalamide;
(b) reacting the product of (a) with sodium hydroxide to produce
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisopthala
mide;
(c) reacting the product of (b) in water and sodium acetate to produce
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide;
and
(d) reacting the product of (c) with an alkylating agent capable of
producing a hydroxyethylated product in the presence of a base and water
to produce ioversol.
The new synthetic route replaces the high cost AAC and BEA components with
chloroacetylchloride (CAC) and an alkylating agent which is capable of
producing a hydroxyethylated product, respectively, thus reducing the
introduction of these components to a more elementary and far less
expensive archetype. Further, except for a small quantity of the polar
aprotic solvent dimethylacetamide (DMAC) utilized in the initial step, the
remaining reactions are conducted in an aqueous reaction medium,
eliminating TCE, DMSO and amyl acetate and their corresponding costs and
environmental difficulties.
DETAILED DESCRIPTION
The current process for producing ioversol is generally depicted in Table
1.
TABLE I
______________________________________
##STR1##
#STR2##
#STR3##
##STR4##
##STR5##
______________________________________
The current general procedure for producing ioversol is as follows:
STEP 1.
Preparation of
5-Amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide
5-Amino-N,N'-bis(2,3-dihydroxpropyl)-2,4,6-triiodoisophthalamide is
dissolved in N,N-diomethylacetamide and acetylated with acetic anhydride,
using 4-dimethylaminopyridine as a catalyst, to produce
5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide. Upon
completion of the reaction, the mixture is diluted with
1,1,2-trichloroethane and washed with aqueous sodium carbonate and aqueous
sodium chloride solutions to remove acetic acid, which is the by-product
of the reaction. The resulting 1,1,2-trichloroethane solution of the
product is used in STEP #2.
STEP 2.
Preparation of
5-Acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalami
de
Most of the solvent (1,1,2-trichloroethane) is distilled from the solution
of 5-amino-N,N'bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide
prepared in STEP #1. The reaction solvent, N,N-dimethylacetamide, is
added. Excess acetoxyacetyl chloride is added and the reaction mixture is
stirred at ca. 40.degree. C. until the reaction is completed.
5-Acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalami
de is formed. 1,1,2-trichloroethane is added to dilute the reaction mixture
and the solution is washed with aqueous sodium bicarbonate and aqueous
sodium chloride solutions to remove acetoxyacetic acid and other
by-products. The resulting organic layer which contains the reaction
product is used in the next step.
STEP 3.
Preparation of
5-[N-(2-Acetoxyethyl)acetoxyacetamido]-N,N'-bis(2,3-diacetoxypropyl)-2,4,6
-triiodoisophthalamide
Solvent (1,1,2-trichloroethane) is distilled from the solution of
5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalami
de prepared in STEP #2. Dimethyl sulfoxide is added as the reaction
solvent. Potassium carbonate and 2-bromoethyl acetate are added and the
mixture is stirred for ca. 10 hours at ca. 40.degree. C. to complete the
reaction to form
5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N'-bis(2,3-diacetoxypropyl)-2,4,6
-triiodoisophthalamide. After the reaction is completed
1,1,2-trichloroethane is added to dilute the mixture. To remove the
inorganic salts and dimethyl sulfoxide in the medium, the mixture is
washed once with deionized water, and twice with aqueous sodium chloride
solution. The organic layer, which contains the product, is then distilled
to remove the solvent and the residue is dissolved in amyl acetate while
the mixture is still hot. The mixture is then cooled and stirred
continuously to complete the crystallization. The reaction product is
collected and dried. After testing, it is used in STEP #4 to prepare crude
ioversol aqueous solution.
STEP 4.
Preparation of N,N'-bis(2,3-dihydroxypropyl
)-5-[N-(2-hydroxyethyl)qlycolamido]-2,4,6-triiodoisophthalamide, (crude
ioversol aqueous solution)
5-[N-(2-Acetoxyethyl)acetoxyacetamido]-N,N'bis(2,3-diacetoxypropy)-2,4,6-tr
iiodoisophthalamide solids are slurried in hot water containing a catalytic
quantity of sulfuric acid. The solid gradually dissolves as it is heated
with the steam on the jacket. The material is hydrolyzed to produce crude
ioversol and acetic acid as a by-product. To remove the acetic acid, clean
steam is sparged into the reactor. The solution volume is maintained
constant by adding deionized water during the reaction and acetic acid
removal. The reaction is tested for completeness of hydrolysis and for the
removal of acetic acid.
The solution which contains ioversol, (crude ioversol aqueous solution) is
cooled and utilized in subsequent purification steps.
The process of the invention for producing ioversol is depicted in Table 2.
TABLE II
______________________________________
##STR6##
#STR7##
##STR8##
##STR9##
______________________________________
The general procedure for the process of the invention involves reacting
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with
chloroacetyl chloride in a polar aprotic solvent.
The resulting product is hydrolyzed with sodium hydroxide. A homogeneous
solution is obtained by adding water. Precipitation is affected to yield
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal
amide. This product is mixed with water and sodium acetate and the pH
adjusted. A base is added as the reaction proceeds in order to maintain pH
at a constant level and produce
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide.
This product from the previous step is subsequently treated in aqueous
solution with a base and reacted with an alkylating agent capable of
producing an hydroxyethylated product. The reaction product is crude
ioversol. The reaction pH is maintained by addition of mineral acid.
Finally, salt and low molecular weight impurities are removed.
Polar aprotic solvents for use with the invention include
dimethylacetamide, acetonitrile, dimethylsulfoxide, dimethylformamide,
tetrahydrofuran, dimethoxyethane, acetonitrile, or combinations thereof.
Suitable bases for use with the water include sodium hydroxide, lithium
hydroxide, ammonium hydroxide, and potassium hydroxide. Alkylating agents
capable of producing a hydroxyethylated product suitable for use with the
invention include 2-chloroethanol, ethylene oxide, ethylene carbonate,
2-bromoethanol, 2-iodoethanol, and 2-tosylethanol.
Specifically, the process of the invention is detailed in the Examples
section of this document.
The following examples illustrate the specific embodiments of the invention
described in this document. As would be apparent to skilled artisans,
various changes and modifications are possible and are contemplated within
the scope of the invention described.
EXAMPLES
Example 1
Preparation of N,N'-bis[2,3-di(2-chloroacetoxy)
propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide
5-Amino-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (84.6 g,
0.12 moles) was dissolved in 172 mL of N,N-dimethylacetamide at 50.degree.
C. The solution was cooled to 10.degree. C. and 62 mL (88.09g, 0.78 moles)
of chloroacetyl chloride were added over 30 minutes. The reaction mixture
was stirred for 3 hours at 50.degree. C. HPLC analysis of the reaction
mixture showed that it contained 99.8%
N,N'-bis[2,3-di-(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triio
do-isophthalamide. The material was carried forward to Example 2 without
further purification.
Example 2
Preparation of
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal
amide
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodo
isophthalamide in N,N-dimethylacetamide, from Example 1, was hydrolyzed by
adding 156 mL of 10N sodium hydroxide solution (1.56 moles). Water (100
mL) was then added to the mixture to give a homogeneous solution. 1N
Hydrochloric acid (59 mL, 0.59 moles) was added to precipitate the
N,N'-bis (2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophtha
lamide. The precipitate was collected and washed with water. The wet
product was dried at 60.degree. C. in a vacuum oven to give 81.69 g of
product, 88.4% yield. The material was 100 % pure by HPLC analysis.
Example 3
Preparation of N,N'-bis[2,3-di(2-chloroacetoxy)
propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide
5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (70.5 g,
0.1 moles) was dissolved in 71 mL of N,N-dimethylacetamide at 50.degree.
C. Acetonitrile (71 mL) was added to the mixture. Chloroacetyl chloride
(52 mL, 73.4 g, 0.65 moles) was added over 30 minutes. The reaction
mixture was stirred for 3 hours at 50.degree. C. HPLC analysis of the
reaction mixture showed that it contained 98.5%
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiod
oisophthalamide. The material was carried forward to Example 4, without
further purification.
Example 4
Preparation of
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal
amide
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodo
isophthalamide in N,N-dimethylacetamide and acetonitrile, from Example 3,
was hydrolyzed by adding 130 mL of 10N sodium hydroxide solution (1.3
moles). Water (36 mL) was then added to the mixture to give a homogeneous
solution. 1N Hydrochloric acid (100 mL, 0.1 moles) was added to
precipitate the
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal
amide. The precipitate was collected and washed with water. The wet product
was dried at 60.degree. C. in a vacuum oven to give 71.6 g of product,
92.2% yield. The material was 100% pure by HPLC analysis.
Example 5
Preparation of
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodo
isophthalamide (39.08 g, 0.05 moles) was suspended in 150 mL of water.
Sodium acetate (32.8 g, 0.4 moles) was added and the pH of the mixture was
adjusted to 6.4 with 1 mL of 12N hydrochloric acid. The mixture was heated
to reflux. The pH of the reaction mixture was maintained at 6.3 to 6.5 by
adding 5N sodium hydroxide solution. At the end of the reaction the
mixture contained 96.4%
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide.
The reaction mixture was cooled to room temperature and the product
precipitated from the reaction mixture. The precipitate was isolated and
washed with water. The solid was dried at 60.degree. C. in a vacuum oven
to give 33 g of product, 94% yield. The material was 97.75% pure by HPLC
analysis.
Example 6
Preparation of
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod
oisophthalamide
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide
(30.0g, 0.039 moles), aqueous sodium hydroxide (50% w/w solution; 7.28 g,
0.091 moles), and deionized water (85 mL) were combined in a 500 mL,
3-necked round bottomed flask equipped with thermometer, overhead stirrer,
and a reflux condenser connected to a 10% aqueous sodium hydroxide trap.
The mixture was heated to 50.degree. C., and the 2-chloroethanol was added
all at once by syringe. Heating was continued for 7 hours. The mixture was
cooled to 10.degree.-15.degree. C., and the reaction was quenched with 5
mL of concentrated hydrochloric acid. By HPLC the reaction mixture
contained 93%
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod
oisophthalamide. The reaction mixture was carried forward without further
processing.
Example 7
Preparation of
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod
oisophthalamide
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide
(17.65 g, 0.023 moles), NaCl (1.3 g, 0.023 moles), NaOAc (15.1 g, 0,184
moles), and deionized water (165 mL) were combined in a 500 mL 4-necked
round bottomed flask equipped with thermometer, overhead stirrer,
air-cooled reflux condenser, and a glass tube attached to an ethylene
oxide gas cylinder. The mixture was cooled to 2.degree. C. with an ice
bath, and ethylene oxide (18.11 g, 0.411 moles) was bubbled subsurface at
a rate of ca. 190 mL/min. The air-cooled condenser and ethylene oxide
inlet tube were removed and replaced with a dry ice condenser attached to
a 10% aqueous NaOH trap. The mixture was heated to 50.degree. C. The pH
was maintained at 10.0 with 1N hydrochloric acid while the mixture was
heterogeneous. When the solids dissolved, the pH was maintained at
9.6-9.8. After 4 hours, the mixture was cooled to room temperature and
quenched first with 1.0N hydrochloric acid (40 mL) and then with
concentrated hydrochloric acid (20 mL) to pH 4.5. The reaction mixture
contained 93% ioversol by HPLC. Assay of the product gave a yield of 17.6
g (94.3%). The reaction mixture was carried forward without further
processing.
Example 8
Removal of salts and other lower molecular weigh impurities from crude
ioversol
A column (2.5 cm diameter, 29 cm height) was packed, using the procedure
recommended by the manufacturer, with Amberlite XAD-16 resin. Crude
ioversol (4.5 g) containing ioversol (45.3%), sodium acetate (40.9%), NaCl
(3.2%), ethylene glycol (10.2%) and other organic impurities was dissolved
in water (12 mL) and loaded into the XAD-16 column. The column was eluted
with water at a flow rate of 3.0 mL per minute. The elution profile was
monitored with a conductivity meter for ionic substances and an UV
detector at 254 nm for ioversol. When the conductivity started to
increase, fractions were collected (30 mL each). The salts and other lower
molecular weight impurities were eluted from the column. The column was
then eluted with a mixture of methanol and water (50/50) which cleanly
effected deadsorption of ioversol from the column in 95-99% yield. The
XAD-16 column may be re-equilibrated with water for reuse. The isolated
ioversol fraction contained less than 5 ppm of ethylene glycol (by HPLC)
and were devoid of ionic impurities (by conductivity analyses).
Although the invention has been described with respect to specific
modifications, the details thereof are not to be construed as limitations,
for it will be apparent that various equivalents, changes and
modifications may be resorted to without departing from the spirit and
scope thereof, and it is understood that such equivalent embodiments are
to be included therein.
Top